Primaxin IV

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Primaxin I.V.

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY
(ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY W ITH
BETA-LACTAMS. THESE REACTIONS ARE MORE APT TO OCCUR IN PERSONS W ITH A HISTORY
OF SENSITIVITY TO MULTIPLE ALLERGENS.

THERE HAVE BEEN REPORTS OF PATIENTS W ITH A HISTORY OF
PENICILLIN HYPERSENSITIVITY W HO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY
REACTIONS W HEN TREATED W ITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY W
ITH PRIMAXIN I.V., CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS
HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS,
AND OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PRIMAXIN SHOULD BE
DISCONTINUED.

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE
EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY
MANAGEMENT, INCLUDING INTUBATION, MAY ALSO BE ADMINISTERED AS INDICATED.

Seizure Potential

Seizures and other CNS adverse experiences, such as
confusional states and myoclonic activity, have been reported during treatment
with PRIMAXIN I.V. (See PRECAUTIONS and ADVERSE REACTIONS.)

Case reports in the literature have shown that
co-administration of carbapenems, including imipenem, to patients receiving
valproic acid or divalproex sodium results in a reduction in valproic acid
concentrations. The valproic acid concentrations may drop below the therapeutic
range as a result of this interaction, therefore increasing the risk of
breakthrough seizures. Increasing the dose of valproic acid or divalproex
sodium may not be sufficient to overcome this interaction. The concomitant use
of imipenem and valproic acid/divalproex sodium is generally not recommended.
Anti-bacterials other than carbapenems should be considered to treat infections
in patients whose seizures are well controlled on valproic acid or divalproex
sodium. If administration of PRIMAXIN I.V. is necessary, supplemental
anticonvulsant therapy should be considered (see PRECAUTIONS: DRUG
INTERACTIONS).

Clostridium difficile associated diarrhea (CDAD)
has been reported with use of nearly all antibacterial agents, including
PRIMAXIN I.V., and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon
leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute
to the development of CDAD.

Hypertoxin producing strains of C. difficile cause
increased morbidity and mortality, as these infections can be refractory to
antimicrobial therapy and may require colectomy. CDAD must be considered in all
patients who present with diarrhea following antibiotic use. Careful medical
history is necessary since CDAD has been reported to occur over two months
after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use
not directed against C. difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation,
antibiotic treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.

PRECAUTIONS

General

CNS adverse experiences such as confusional states,
myoclonic activity, and seizures have been reported during treatment with
PRIMAXIN I.V., especially when recommended dosages were exceeded. These
experiences have occurred most commonly in patients with CNS disorders (e.g.,
brain lesions or history of seizures) and/or compromised renal function.
However, there have been reports of CNS adverse experiences in patients who had
no recognized or documented underlying CNS disorder or compromised renal
function.

When recommended doses were exceeded, adult patients with
creatinine clearances of ≤ 20 mL/min/1.73 m², whether or not undergoing
hemodialysis, had a higher risk of seizure activity than those without
impairment of renal function. Therefore, close adherence to the dosing
guidelines for these patients is recommended. (SeeDOSAGE AND ADMINISTRATION.)

For patients on hemodialysis, PRIMAXIN I.V. is
recommended only when the benefit outweighs the potential risk of seizures.

Close adherence to the recommended dosage and dosage
schedules is urged, especially in patients with known factors that predispose
to convulsive activity. Anticonvulsant therapy should be continued in patients
with known seizure disorders. If focal tremors, myoclonus, or seizures occur,
patients should be evaluated neurologically, placed on anticonvulsant therapy
if not already instituted, and the dosage of PRIMAXIN I.V. re-examined to
determine whether it should be decreased or the antibiotic discontinued.

As with other antibiotics, prolonged use of PRIMAXIN I.V.
may result in overgrowth of nonsusceptible organisms. Repeated evaluation of
the patient's condition is essential. If superinfection occurs during therapy,
appropriate measures should be taken.

Prescribing PRIMAXIN I.V. in the absence of a proven or
strongly suspected bacterial infection or a prophylactic indication is unlikely
to provide benefit to the patient and increases the risk of the development of
drug-resistant bacteria.

Laboratory Tests

While PRIMAXIN I.V. possesses the characteristic low
toxicity of the beta-lactam group of antibiotics, periodic assessment of organ
system functions, including renal, hepatic, and hematopoietic, is advisable
during prolonged therapy.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long term studies in animals have not been performed to
evaluate carcinogenic potential of imipenemcilastatin. Genetic toxicity studies
were performed in a variety of bacterial and mammalian tests in vivo and in
vitro. The tests used were: V79 mammalian cell mutagenesis assay (imipenem-cilastatin
sodium alone and imipenem alone), Ames test (cilastatin sodium alone and
imipenem alone), unscheduled DNA synthesis assay (imipenem-cilastatin sodium)
and in vivo mouse cytogenetics test (imipenem-cilastatin sodium). None of these
tests showed any evidence of genetic alterations.

Reproductive tests in male and female rats were performed
with imipenem-cilastatin sodium at intravenous doses up to 80 mg/kg/day and at
a subcutaneous dose of 320 mg/kg/day, approximately equal to the highest
recommended human dose of the intravenous formulation (on a mg/m² body
surface area basis). Slight decreases in live fetal body weight were restricted
to the highest dosage level. No other adverse effects were observed on
fertility, reproductive performance, fetal viability, growth or postnatal
development of pups.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Teratology studies with cilastatin sodium at doses of 30,
100, and 300 mg/kg/day administered intravenously to rabbits and 40, 200, and
1000 mg/kg/day administered subcutaneously to rats, up to approximately 1.9 and
3.2 times 2 the maximum recommended daily human dose (on a mg/m² body surface
area basis) of the intravenous formulation of imipenem-cilastatin sodium (50
mg/kg/day) in the two species, respectively, showed no evidence of adverse
effect on the fetus. No evidence of teratogenicity was observed in rabbits
given imipenem at intravenous doses of 15, 30 or 60 mg/kg/day and rats given
imipenem at intravenous doses of 225, 450, or 900 mg/kg/day, up to
approximately 0.4 and 2.9 times2 the maximum recommended daily human dose (on a
mg/m² body surface area basis) in the two species, respectively.

Teratology studies with imipenem-cilastatin sodium at
intravenous doses of 20 and 80, and a subcutaneous dose of 320 mg/kg/day, up to
0.5 times2 (mice) to approximately equal to (rats) the highest
recommended daily intravenous human dose (on a mg/m² body surface area basis)
in pregnant rodents during the period of major organogenesis, revealed no
evidence of teratogenicity.

Imipenem-cilastatin sodium, when administered
subcutaneously to pregnant rabbits at dosages equivalent to the usual human
dose of the intravenous formulation and higher (1000-4000 mg/day), caused body
weight loss, diarrhea, and maternal deaths. W hen comparable doses of
imipenem-cilastatin sodium were given to non-pregnant rabbits, body weight
loss, diarrhea, and deaths were also observed.

This intolerance is not unlike that seen with other
beta-lactam antibiotics in this species and is probably due to alteration of
gut flora.

A teratology study in pregnant cynomolgus monkeys given
imipenem-cilastatin sodium at doses of 40 mg/kg/day (bolus intravenous
injection) or 160 mg/kg/day (subcutaneous injection) resulted in maternal
toxicity including emesis, inappetence, body weight loss, diarrhea, abortion,
and death in some cases. In contrast, no significant toxicity was observed when
non-pregnant cynomolgus monkeys were given doses of imipenem-cilastatin sodium
up to 180 mg/kg/day (subcutaneous injection). W hen doses of imipenemcilastatin
sodium (approximately 100 mg/kg/day or approximately 0.6 times2 the maximum recommended
daily human dose of the intravenous formulation) were administered to pregnant
cynomolgus monkeys at an intravenous infusion rate which mimics human clinical
use, there was minimal maternal intolerance (occasional emesis), no maternal
deaths, no evidence of teratogenicity, but an increase in embryonic loss
relative to control groups.

No adverse effects on the fetus or on lactation were
observed when imipenem-cilastatin sodium was administered subcutaneously to
rats late in gestation at dosages up to 320 mg/kg/day, approximately equal to
the highest recommended human dose (on a mg/m² body surface area basis).

There are, however, no adequate and well-controlled
studies in pregnant women. PRIMAXIN I.V. should be used during pregnancy only
if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers

It is not known whether imipenem-cilastatin sodium is
excreted in human milk. Because many drugs are excreted in human milk, caution
should be exercised when PRIMAXIN I.V. is administered to a nursing woman.

Pediatric Use

Use of PRIMAXIN I.V. in pediatric patients, neonates to
16 years of age, is supported by evidence from adequate and well-controlled
studies of PRIMAXIN I.V. in adults and by the following clinical studies and
published literature in pediatric patients: Based on published studies of 1783
pediatric patients ≥ 3 months of age (with non-CNS infections), the
recommended dose of PRIMAXIN I.V. is 15-25 mg/kg/dose administered every six
hours. Doses of 25 mg/kg/dose in patients 3 months to < 3 years of age, and
15 mg/kg/dose in patients 3-12 years of age were associated with mean trough
plasma concentrations of imipenem of 1.1±0.4 μg/mL and 0.6±0.2 μg/mL
following multiple 60-minute infusions, respectively; trough urinary
concentrations of imipenem were in excess of 10 μg/mL for both doses.
These doses have provided adequate plasma and urine concentrations for the
treatment of non-CNS infections. Based on studies in adults, the maximum daily
dose for treatment of infections with fully susceptible organisms is 2.0 g per
day, and of infections with moderately susceptible organisms (primarily some
strains of P. aeruginosa) is 4.0 g/day. (See DOSAGE AND ADMINISTRATION,
Table 3.) Higher doses (up to 90 mg/kg/day in older children) have been used in
patients with cystic fibrosis. (See DOSAGE AND ADMINISTRATION.)

Based on studies of 1354 pediatric patients
≤ 3 months of age (weighing ≥ 1,500 g), the following dosage schedule
is recommended for non-CNS infections:

In a published dose-ranging study of smaller premature
infants (670-1,890 g) in the first week of life, a dose of 20 mg/kg q12h by
15-30 minutes infusion was associated with mean peak and trough plasma imipenem
concentrations of 43 μg/mL and 1.7 μg/mL after multiple doses,
respectively. However, moderate accumulation of cilastatin in neonates may
occur following multiple doses of PRIMAXIN I.V. The safety of this accumulation
is unknown.

PRIMAXIN I.V. is not recommended in pediatric patients
with CNS infections because of the risk of seizures. PRIMAXIN I.V. is not
recommended in pediatric patients < 30 kg with impaired renal function, as no
data are available.

Geriatric Use

Of the approximately 3600 subjects ≥ 18 years of age
in clinical studies of PRIMAXIN I.V., including postmarketing studies,
approximately 2800 received PRIMAXIN I.V. Of the subjects who received PRIMAXIN
I.V., data are available on approximately 800 subjects who were 65 and over,
including approximately 300 subjects who were 75 and over. No overall
differences in safety or effectiveness were observed between these subjects and
younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the
kidney, and the risk of toxic reactions to this drug may be greater in patients
with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and it may be
useful to monitor renal function.

No dosage adjustment is required based on age (see CLINICAL
PHARMACOLOGY, Adults). Dosage adjustment in the case of renal
impairment is necessary (seeDOSAGE AND ADMINISTRATION, Reduced
Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight
< 70 kg).

REFERENCES

2 Based on patient body surface area of 1.6 m²
(weight of 60 kg). 3Two
patients were less than 3 months of age. 4One patient was greater than 3 months of age.

Last reviewed on RxList: 12/30/2014
This monograph has been modified to include the generic and brand name in many instances.